In this project we will conduct a clinical trial in patients with relapsed B cell and T cell lymphomas. It is based[unreadable] on a new method of therapeutic vaccination for lymphoma, which we developed in murine models. In mice,[unreadable] advanced systemic tumors can be temporarily eliminated by inducing tumor cell death by chemotherapy. In[unreadable] contrast, long-term tumor elimination is achieved by chemotherapy followed by local intralesional injection of[unreadable] either dendritic cells or a CpG oligonucleotide, an activator of resident dentritic cells (in situ vaccination).[unreadable] Either maneuver alone, cell death induction or intralesional injection, has no long-term effect. The[unreadable] combination results in uptake and processing of tumor antigens by the dendritic cells and subsequent[unreadable] induction of a systemic T cell immune response which is capable of eliminating tumor at distant sites.[unreadable] In the clinical trial, local tumor death will be induced by low dose radiotherapy and CpG will be injected into[unreadable] the same local lesion. Patients will be monitored for anti tumor immune responses and for tumor regression[unreadable] at distant sites. Direct signaling effects of CpG oligonucleotides on the human tumors will be studied in[unreadable] collaboration with Dr. Nolan in Project 2, and related to the clinical effects seen in patients. We are fortunate[unreadable] to have available for these studies a clinical grade CpG compound which has already been safety tested,[unreadable] which has proven to be effective in humans as a vaccine adjuvant and which has shown preliminary[unreadable] evidence of anti tumor efficacy in trials at Stanford in patients with cutaneous T cell lymphoma.[unreadable] In parallel with these clinical trials we will further develop the maneuver of in situ vaccination in animal[unreadable] models by studying its mechanism and by combining immunostimulatory agents to optimize their anti tumor[unreadable] effects. Lessons learned from the animal model will be translated into the design of future clinical trials.